Process for preparing cross-bridged tetraaza macrocycles

ABSTRACT

The present invention relates to a process for preparing a cross-bridged tetraaza macrocyclic ligands having formula (I), wherein each R is independently C 1 -C 22  linear alkyl, C 1 -C 22  branched alkyl, C 7 -C 22  alkylenearyl, C 8 -C 22  alkyl substituted alkylenearyl, and mixtures thereof; each index n is independently from 0 to 3, by contacting the a di-quaternary cis tetracycle precursor with as little as one equivalent of a borohydride reducing agent. The present process eliminates the need to use up to a twenty fold excess of reducing agent thereby further eliminating the need for work-up conditions which liberate significant amounts of hydrogen gas and which requires the disposal of large amounts of boron waste products.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a national stage entry under 35 U.S.C. § 371 ofPCT/US99/26540, filed Nov. 9, 1999, which claims the benefit of U.S.Provisional Application No. 60/108,380 filed Nov. 13, 1998 (nowabandoned).

FIELD OF THE INVENTION

The present invention relates to an improved process for preparingcross-bridged tetraaza macrocycles, said macrocycles suitable as ligandsfor use in preparing transition metal complexes. The present inventionprovides a process which is well suited for use in industrial and othercommercial preparations of the herein described crossed-bridgedmacrocycles.

BACKGROUND OF THE INVENTION

Tetraaza macrocyclics, for example, cyclam, have been prepared innumerous ways, however, there is a paucity of information relating tothe preparation of cross-bridged tetraaza macrocyclics inter alia1,5,8,12-tertaaza-bicyclo[6.6.2]hexadecane. Recently, bis N-substitutedtetraaza macrocyclics inter alia 5,12 dialkyl or dialkylenearyl1,5,8,12-tetraaza-bicyclo[6.6.2]hexadecanes have found wideapplicability as ligands especially in the area of transition metalcatalysts inter alia bleach catalysts.

WO 98/39335 A1 “Improved Methods of Making Cross-BridgedMacropoly-cycles” discloses a rational procedure for preparing crossbridged macropolycyclic ligands which is amenable to high yieldsnecessary for industrial scale-up. However, the reductive ring cleavagestep which results in bicyclo bridged-ring formation utilizes a largeexcess of a borohydride reducing agent. This excess of reducing agentcan place constraints on the formulator. For example, when manufacturingthe disclosed ligands on a industrial scale, any excess of reagentbeyond the stoichiometric amount places an increased cost burden on theformulator. In addition, the proper recovery and disposal of boron wasteproducts adds cost to the process. Excess borohydride requiresneutralization which involves the use of acid and the evolution of largequantities of hydrogen gas.

Therefore, a need exists for a highly quantitative, stoichiometricprocess for preparing cross-bridged macropolycyclic ligands.

SUMMARY OF THE INVENTION

The present invention meets the aforementioned needs in that it has beensurprisingly discovered that approximately one mole equivalent of aborohydride reducing agent is necessary to convert cis-tetracycles tocross bridged macropolycyclic ligands.

A first aspect of the present invention relates to a process forpreparing a cross-bridged tetraaza macrocyclic ligand having theformula:

wherein each R is independently C₁-C₂₂ linear alkyl, C₁-C₂₂ branchedalkyl, C₇-C₂₂ alkylenearyl, C₈-C₂₂ alkyl substituted alkylenearyl, andmixtures thereof; each index n is independently from 0 to 3, saidprocess comprising the steps of:

a) reacting one mole equivalent of a tetraaza macrocyclic ligandprecursor having the formula:

 wherein X⁻ is an anion which provides charge neutrality, with fromabout 1 mole equivalent to about 3.5 mole equivalents of a reducingagent having the formula MBH₄ wherein M is selected from the groupconsisting of lithium, sodium, potassium, and mixtures thereof; at a pHof at least about 11 to form a macrocyclic ligand; and

b) optionally isolating said macrocyclic ligand.

All percentages, ratios and proportions herein are by weight, unlessotherwise specified. All temperatures are in degrees Celsius (° C.)unless otherwise specified. All documents cited are in relevant part,incorporated herein by reference.

DETAILED DESCRIPTION OF THE INVENTION

Until the disclosure of WO 98/39335 A1 there was no process forpreparing cross-bridged tetraaza macrocyclic ligands, especially ligandssuitable for use in preparing catalysts inter alia manganese (II) bleachcatalysts, which was suitable for industrial application.

WO 98/39098 A1 “Catalysts and Methods for Catalytic Oxidation” publishedSep. 11, 1998 discloses cross-bridged tetraaza macrocyclic ligands andtransition metal complexes formed therefrom. These transition metalcomplexes serve as oxidation catalysts which have a wide range of usesinter alia as bleaching catalysts for use in removing stains fromfabric. A preferred catalyst is5,12-dimethyl-1,5,8,12-tertaaza-bicyclo[6.6.2]hexadecane manganese (II)chloride which comprises the cross-bridged ligand 5,12-dimethyl-1,5,8,12-tertaaza-bicyclo[6.6.2]hexadecane. WO 98/39335 A1 describes thepreparation of this ligand wherein 12 moles of NaBH₄ is used to cleave abis(quaternary-N-methyl) cis-tetracycle precursor to5,12-dimethyl-1,5,8,12-tertaaza-bicyclo[6.6.2]hexadecane. The presentinvention stabilizes the borohydride by conducting the step (a) at a pHof at least about 11.

It has been surprisingly discovered that this transformation andtransformations which convert other cis-tetracycles to cross-bridgedmacrocycles can be conducted in nearly quantitative yield with a nearstoichiometric amount of borohydride reducing agent.

The process of the present invention relates to the reductive cleavageof a cis-tetracycle having the formula:

wherein each R is independently C₁-C₂₂ linear alkyl, C₁-C₂₂ branchedalkyl, C₇-C₂₂ alkylenearyl, C₈-C₂₂ alkyl substituted alkylenearyl, andmixtures thereof; X represents an anion which provides electronicneutrality; each index n is independently from 0 to 3. The reductivering cleavage results in a tetraaza macrocyclic ligand having theformula:

wherein R and the index n are the same as defined herein above.

X is an anion which serves to provide electronic neutrality to thebis-quaternary cis tetracycle. Those of ordinary skill in the artrecognize that the term “electronic neutrality” refers to “a sufficientamount of an anionic species which satisfies the molecular chargebalance requirements” and that a mixture of mono-, di-, tri-, etc.electronic species may be use herein. X preferably has unit negativecharge, for example, halogen, tosylate methylsulfate. However, X mayhave more than one negative charge, for example, sulfate, in which casethe formulator requires only half the amount necessary when using a unitnegative-charged anion.

For the purposes of the present invention the term “linear alkyl” isdefined as “any linear alkyl chain” non-limiting examples of whichinclude methyl, ethyl, n-propyl, n-decyl, etc. For the purposes of thepresent invention the term “branched alkyl” is defined herein as “anyalkyl chain which has one or more alkyl branches” non-limiting examplesof which included, 2-ethylhexyl, 3-methylpentyl, isopropyl, isobutyl,etc. For the purposes of the present invention the term “alkylenearyl”is defined as a unit having the formula:

—(CH₂)_(x)—Ar

wherein Ar represents an aromatic moiety having from 6 to 14 carbonatoms and x has the value from 1 to 16. Non-limiting examples of Arunits are phenyl and naphthyl. For the purposes of the present inventionthe term “alkyl substituted alkylenearyl” is defined as “an alkylenearylunit wherein one or more carbons atoms of the Ar unit has an alkyl unitreplacing the hydrogen atom.” Non-limiting examples of alkyl substitutedalkylenearyl Ar units include 4-methylphenyl (toluyl) and3,5-di-tert-butylphenyl. For alkyl substituted alkylenearyl units theindex x is from 1 to 15.

In its basic form, the process of the present invention comprises areduction step and an optional isolation and/or purification step. Thereduction step is necessary in that the required chemical transformationis performed in this step, however, the isolation and/or purificationstep is optional. The formulator may find that isolation of thecross-bridged macrocycle is not a necessary step if the next usage ofthe formed ligand is, for example, formation of a metal complex, andthis succeeding step can be successfully performed on the crude,un-isolated product which is still in the reduction step admixture.

STEP (a) Reductive Cleavage

Step (a) comprises the borohydride (BH₄ ⁻) reductive cleavage asoutlined in the following scheme:

wherein the cis-tetracycle bis quaternary salt is converted to thecross-bridged tetraaza macrocycle.

The pH under which Step (a) must be conducted is at least 11, preferablyat least 12. Preferably the base which is used to adjust the pH is inthe form of an aqueous solution. Preferred bases are selected from thegroup consisting of potassium carbonate, sodium carbonate, sodiumhydroxide, potassium hydroxide, and mixtures thereof. It is satisfactoryto use a sufficient amount of 1 M (molar) aqueous base to adjust the pHto the required level. A convenient and preferred base is potassiumcarbonate.

Preferably Step (a) is conducted in the presence of a solvent.Non-limiting examples of solvents include benzene, toluene, methanol,ethanol, n-propanol, isopropanol, diethyl ether, tetrahydrofuran, andmixtures thereof; prefered solvents are selected from the groupconsisting of ethanol, n-propanol, isopropanol, and mixtures thereof.When a solvent is present and the base is in the form of an aqueoussolution, the ratio of said volume of aqueous base, preferably 1 molaraqueous base, to said solvent is from about 1:10 to about 1:1,preferably the ratio of the volume of aqueous base to solvent is 1:4. Itis desirable, but not a requirement, that the aqueous base and solventform a two phase system.

The reducing agent for the process of the present invention isborohydride, BH₄ ⁻. Non-limiting examples of reducing agents which arepreferred for the process of the present invention include reducingagents having the formula MBH₄ wherein M is selected from the groupconsisting of lithium, sodium, potassium, and mixtures thereof;preferably M is sodium (sodium borohydride). Surprisingly, under theconditions of the present process, only the stoichiometrically required1 mole equivalent of sodium borohydride (corresponding to two moles ofH₂) is needed to accomplish the desired transformation. However, up to3.5 mole equivalents can be suitably used, especially in continuousprocesses wherein the aqueous phase is recycled and the amount ofreducing agent which is consumed during the chemical ring cleavage isreplace prior to introduction of another batch of starting material. Apreferred embodiment, which balances time, reaction temperature, andyield, uses 2 mole equivalents of borohydride reducing agent. Thislimitation removes the need for large amounts of acid to destroy theunused borohydride, thereby eliminating the unnecessary release ofexcess hydrogen gas during work-up and optional isolation.

Step (a) may be conducted at any temperature from about 10° C.,preferably from about room temperature, more preferably from about 40°C. to about 70° C., more preferably to about 50° C.

In a preferred embodiment of the process of the present invention,sufficient 1 M base is admixed with ethanol in a suitable reactionvessel to form a two phase system which is mechanically stirred andwarmed to about 50° C. Concurrently and in a portion-wise manner overequal time intervals, 2 equivalents of sodium borohydride and a cistetracycle are added to the reaction vessel maintaining the temperatureat about 50° C. After addition of the reagents is complete, the reactionis monitored using any convenient means, for the consumption of thecis-tetracycle. Once the starting material is consumed the organic phaseis decanted and the product isolated by normal procedures.

The following is a non-limiting example of the process of the presentinvention used to fragment a specific tetracycle.

EXAMPLE 1 Preparation of5,12-dimethyl-1,5,8,12-tertaaza-bicyclo[6.6.2]hexadecane

Distilled water (25 mL) and potassium carbonate (13.8 g) are combined ina 250 mL round bottomed flask. Absolute ethanol (75 mL) is added and theresulting two phase solution is stirred and heated to about 60° C.Sodium borohydride (1.60 g., 42.3 mmol) and the cis-tetracycle havingthe formula:

wherein X is methylsulfate, (10.0 g, 21.1 mmol) is added to thesolution. The reaction is stirred at 60° C. for 75 minutes. The reactionmixture is transferred to a separatory funnel and the ethanol layercollected. The ethanol is evaporated under reduced pressure and affordsa tan-colored oily solid. The crude material is treated with 5N KOH (5mL) until dissolved and the aqueous solution extracted with toluene(2×50 mL). The toluene is removed in vacuo to afford a crude oil whichis subsequently distilled at about 0.2 mm Hg to yield 5.2 g (95%) of5,12-dimethyl-1,5,8,12-tertaaza-bicyclo[6.6.2]hexadecane as a colorlessoil.

What is claimed is:
 1. A process for preparing a tetraaza macrocyclicligand having the formula:

wherein each R is independently C₁-C₂₂ linear alkyl, C₁-C₂₂ branchedalkyl, C₇-C₂₂ alkylenearyl, C₈-C₂₂ alkyl substituted alkylenearyl, andmixtures thereof; each index n is independently from 0 to 3, saidprocess comprising the steps of: a) reacting one mole equivalent of atetraaza macrocyclic ligand precursor having the formula:

 wherein X⁻ is an anion which provides charge neutrality, with from 1mole equivalent to 3 mole equivalents a reducing agent having theformula MBH₄ wherein M is selected from the group consisting of lithium,sodium, potassium, and mixtures thereof; at a pH of at least 11 to forma macrocyclic ligand; and b) optionally isolating said macrocyclicligand.
 2. A process according to claim 1 wherein R is C₁-C₈ linearalkyl, C₇-C₁₀ alkylenearyl, C₈-C₁₀ alkyl substituted alkylenearyl, andmixtures thereof.
 3. A process according to claim 1 wherein R is C₁-C₄linear alkyl, benzyl, and mixtures thereof.
 4. A process according toclaim 3 wherein R is methyl.
 5. A process according to claim 4 whereintwo of the indices n are equal to 0 and two of the indices n are equalto
 1. 6. A process according to claim 5 wherein said tetraazamacrocyclic ligand formed by said process has the formula:


7. A process according to claim 6 wherein said reducing agent is NaBH₄.8. A process according to claim 7 wherein said reducing agent is presentin the amount of 2 mole equivalents.
 9. A process according to claim 8wherein said pH of step (a) is at least
 12. 10. A process according toclaim 9 wherein step (a) is conducted in the presence of one or moresolvents.
 11. A process according to claim 10 wherein step (a) isconducted in the presence of water and one or more solvents.
 12. Aprocess for preparing a tetraaza macrocyclic ligand having the formula:

wherein R is C₁-C₂₂ linear alkyl, C₁-C₂₂ branched alkyl, C₇-C₂₂alkylenearyl, C₈-C₂₂ alkyl substituted alkylenearyl, and mixturesthereof; each index n is independently from 0 to 3, said processcomprising the steps of: a) combining in a reaction vessel a one molarsolution of base and a solvent, wherein the ratio of said base to saidsolvent is from 1:10 to 1:1; to form a two phase solution; b) adding tosaid two phase solution one mole equivalent of a tetraaza macrocyclicligand precursor having the formula:

 wherein X⁻ is an anion which provides charge neutrality, and from 1mole equivalent to 3 mole equivalents of a reducing agent having theformula MBH₄ wherein M is selected from the group consisting of lithium,sodium, potassium, and mixtures thereof; at a pH of at least 11 to forma macrocyclic ligand; c) separating the aqueous and non-aqueous phases;and d) optionally isolating said macrocyclic ligand.
 13. A process forpreparing a tetraaza macrocyclic ligand having the formula:

wherein R is C₁-C₂₂ linear alkyl, C₁-C₂₂ branched alkyl, C₇-C₂₂alkylenearyl, C₈-C₂₂ alkyl substituted alkylenearyl, and mixturesthereof; each index n is independently from 0 to 3, said processcomprising the steps of: a) combining in a reaction vessel a one molarsolution of base, said base selected from the group consisting ofpotassium carbonate, sodium carbonate, sodium hydroxide, potassiumhydroxide, and mixtures thereof; and a solvent, said solvent selectedfrom the group consisting of benzene, toluene, methanol, ethanol,n-propanol, isopropanol, diethyl ether, tetrahydrofuran, and mixturesthereof; wherein the ratio of said base to said solvent is from 1:10 to1:1; to form a two phase solution; b) adding to said two phase solution,at a temperature of from 10° C. to 70° C., a tetraaza macrocyclic ligandprecursor having the formula:

 wherein X⁻ is an anion which provides charge neutrality, with from 1mole equivalent to 3 mole equivalents a reducing agent having theformula MBH₄ wherein M is selected from the group consisting of lithium,sodium, potassium, and mixtures thereof; at a pH of at least 11 to forma macrocyclic ligand; c) separating the aqueous and non-aqueous phases;and d) optionally isolating said macrocyclic ligand from saidnon-aqueous phase.
 14. A process for preparing5,12-dimethyl-1,5,8,12-tertaaza-bicyclo[6.6.2]hexadecane having theformula:

said process comprising the steps of: a) combining in a reaction vessela one molar solution of base, said base selected from the groupconsisting of potassium carbonate, sodium carbonate, and mixturesthereof; and a solvent, said solvent selected from the group consistingof ethanol, n-propanol, isopropanol, and mixtures thereof; wherein theratio of the volume of said base to said volume of solvent is 1:4; toform a two phase solution comprising an aqueous phase and a solventphase; b) adding to said two phase solution, at a temperature of from50° C., a macrocyclic ligand precursor having the formula:

 wherein X⁻ is an anion which provides charge neutrality, together with2 mole equivalents of NaBH₄ at a pH of at least 12 to form4,11-dimethyl-1,4,8,11-tetraaza-bicyclo[6.6.2]hexadecane; c) separatingfrom said two phase system said solvent phase; and d) isolating fromsaid solvent phase5,12-dimethyl-1,5,8,12-tertaaza-bicyclo[6.6.2]hexadecane.